The antagonisms between the essential divalent metals, calcium, magnesium, and zinc, and the divalent metal carcinogens, lead, nickel and cadmium, are under investigation in carcinogenesis, toxicity, metabolism and biochemical studies. Magnesium has been shown to inhibit lung adenoma formation in lead- and nickel-treated strain A mice as well as nickel-induced sarcomas in rats. Part of the protection afforded by magnesium against the tumorigenic activity of nickel in mice appears due to the diminished accumulation of the carcinogenic metal in the nuclei and cytosol of pulmonary cells. Nickel-induced enhancement of pulmonary DNA synthesis was abolished by magnesium. In the muscles of rats magnesium prevented the initial necrosis produced by injection of a carcinogenic dose of nickel subsulfide. Zinc deficiency caused a marked enhancement of cadmium accumulation in tissues. Excess zinc was found to markedly reduce cadmium uptake into target cells of cadmium and nickel binding to DNA was found to be inhibited by zinc, magnesium, manganese, calcium and copper. To the extent that the biological data are available, such inhibition of DNA binding was found to be proportional to the preventative effects of the same physiological metals on cadmium and nickel carcinogenesis. The effects of calcium on lead-, cadmium-, or nickel-induced carcinogenesis are inconsistent. Extension of the mechanisms underlying the antagonistic effects of the physiologically essential divalent metals against tumor formation by nickel, lead, and cadmium in other target sites will be explored.